Download PDF
Thromb Haemost 2011; 105(02): 371-378
DOI: 10.1160/TH10-06-0342
New Technologies, Diagnostic Tools and Drugs
Schattauer GmbH

Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays

Tomas L. Lindahl
1   Department of Clinical and Experimental Medicine, Clinical Chemistry, University of Linköping, Sweden
,
Fariba Baghaei
2   Department of Medicine, Coagulation Centre, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Inger Fagerberg Blixter
3   Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy, University of Gothenburg, Sweden
,
Kerstin M. Gustafsson
1   Department of Clinical and Experimental Medicine, Clinical Chemistry, University of Linköping, Sweden
,
Lennart Stigendal
2   Department of Medicine, Coagulation Centre, Sahlgrenska University Hospital, Gothenburg, Sweden
,
Margareta Sten-Linder
4   Department of Molecular Medicine and Surgery, Clinical Chemistry, Karolinska Institutet, Stockholm, Sweden
,
Karin Strandberg
5   University and Regional Laboratories Region Scania, Clinical Chemistry, Malmö, Sweden
,
Andreas Hillarp
5   University and Regional Laboratories Region Scania, Clinical Chemistry, Malmö, Sweden
,
and from the expert group on coagulation of the External Quality Assurance in Laboratory Medicine in Sweden › Author Affiliations
Further Information

Publication History

Received: 03 June 2010

Accepted after major revision: 18 October 2010

Publication Date:
25 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Dabigatran is an oral, reversible thrombin inhibitor that has shown promising results in large clinical trials. Laboratory monitoring is not needed but the effects on common coagulation assays are incompletely known. Dabigatran was added to plasma from healthy subjects in the concentration range 0–1,000 μg/l and analysed using several reagents for activated thromboplastin time (APTT), prothrombin time (PT), fibrinogen, antithrombin, and activated protein C resistance. Typical trough concentrations are about 50 μg/l, peak concentrations 100–300 μg/l. At 100 μg/l all APTT-results were prolonged. The concentration required to double APTT ranged between 227 and 286 μg/l, the responses for all five reagents were similar. PT-reagents were much less affected with almost no samples above INR 1.2 at 100 μg/l. The effect was sample dilution dependent with PT Quick type more sensitive than PT Owren type methods. If a patient on dabigatran has prolonged APTT, >90 seconds, and Quick PT INR>2 or Owren PT INR>1.5 over-dosing or accumulation of dabigatran should be considered. Two of four fibrinogen reagents underestimated the fibrinogen concentration considerably at expected peak concentration. Methods based on inhibition of thrombin over-estimated the antithrombin concentration, but not Xa-based. The APC-resistance methods over-estimated the APC-ratio, which may lead to miss-classification of factor V Leiden patients as being normal. Different coagulation assays, and even different reagents within an assay group, display variable effects at therapeutic concentrations of dabigatran. Some of these assay variations are of clinical importance, thus knowledge is needed for a correct interpretation of results.

Keywords

Dabigatran - thrombin inhibitor - interference - anticoagulant - coagulation assays
 

  • References

  • 1 Rost S, Fregin A, Ivaskevicius V. et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 42: 537-541.
    PubMedSearch in Google Scholar
  • 2 Osman A, Enstrom C, Arbring K. et al. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost 2006; 4: 1723-1729.
    CrossrefPubMedSearch in Google Scholar
  • 3 Schulman S, Wahlander K, Lundstrom T. et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713-1721.
    CrossrefPubMedSearch in Google Scholar
  • 4 Eriksson BI, Bergqvist D, Kalebo P. et al. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002; 360: 1441-1447.
    CrossrefPubMedSearch in Google Scholar
  • 5 Agnelli G, Eriksson BI, Cohen AT. et al. Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran. Thromb Res 2009; 123: 488-497.
    CrossrefPubMedSearch in Google Scholar
  • 6 Mattsson C, Menschiek-Lundin A, Wahlander K. et al. Effect of melagatran on prothrombin time assays depends on the sensitivity of the thromboplastin and the final dilution of the plasma sample. Thromb Haemost 2001; 86: 611-615.
    Thieme ConnectPubMedSearch in Google Scholar
  • 7 Harder S, Graff J, Klinkhardt U. et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and Ecarin Clotting Time. Thromb Haemost 2004; 91: 1137-1145.
    Thieme ConnectPubMedSearch in Google Scholar
  • 8 Walenga JM, Drenth AF, Mayuga M. et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing. Clin Appl Thromb Hemost 2008; 14: 325-331.
    CrossrefPubMedSearch in Google Scholar
  • 9 Fenyvesi T, Joerg I, Harenberg J. Influence of lepirudin, argatroban, and melagatran on prothrombin time and additional effect of oral anticoagulation. Clin Chem 2002; 48: 1791-1794.
    PubMedSearch in Google Scholar
  • 10 Siegmund R, Boer K, Poeschel K. et al. Influence of direct thrombin inhibitor argatroban on coagulation assays in healthy individuals, patients under oral anticoagulation therapy and patients with liver dysfunction. Blood Coagul Fibrinolysis 2008; 19: 288-293.
    CrossrefPubMedSearch in Google Scholar
  • 11 Fenyvesi T, Jorg I, Weiss C. et al. Effects of lepirudin, argatroban and melagatran and additional influence of phenprocoumon on ecarin clotting time. Thromb Res 2003; 111: 89-94.
    CrossrefPubMedSearch in Google Scholar
  • 12 Hursting MJ, Zehnder JL, Joffrion JL. et al. The International Normalized Ratio during concurrent warfarin and argatroban anticoagulation: differential contributions of each agent and effects of the choice of thromboplastin used. Clin Chem 1999; 45: 409-412.
    PubMedSearch in Google Scholar
  • 13 Eriksson BI, Dahl OE, Rosencher N. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet 2007; 370: 949-956.
    CrossrefPubMedSearch in Google Scholar
  • 14 Eriksson BI, Dahl OE, Rosencher N. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007; 5: 2178-2185.
    CrossrefPubMedSearch in Google Scholar
  • 15 Connolly SJ, Ezekowitz MD, Yusuf S. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedSearch in Google Scholar
  • 16 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedSearch in Google Scholar
  • 17 Stangier J, Eriksson BI, Dahl OE. et al. Pharmacokinetic profile of the oral direct thrombin inhibitor dabigatran etexilate in healthy volunteers and patients undergoing total hip replacement. J Clin Pharmacol 2005; 45: 555-563.
    CrossrefPubMedSearch in Google Scholar
  • 18 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Pharmacokinet 2008; 47: 285-295.
    CrossrefPubMedSearch in Google Scholar
  • 19 Lindahl TL, Egberg N, Hillarp A. et al. INR calibration of Owren-type prothrombin time based on the relationship between PT% and INR utilizing normal plasma samples. Thromb Haemost 2004; 91: 1223-1231.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Stangier J, Stahle H, Rathgen K. et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet 2008; 47: 47-59.
    CrossrefPubMedSearch in Google Scholar
  • 22 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate – a novel, reversible, oral direct thrombin inhibitor: Interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Blech S, Ebner T, Ludwig-Schwellinger E. et al. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos 2008; 36: 386-399.
    CrossrefPubMedSearch in Google Scholar
  • 24 Stangier J, Rathgen K, Stahle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
    CrossrefPubMedSearch in Google Scholar
  • 25 Stangier J, Rathgen K, Stahle H. et al. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 2010; 49: 259-268.
    CrossrefPubMedSearch in Google Scholar
  • 26 Molinaro RJ, Szlam F, Levy JH. et al. Low plasma fibrinogen levels with the Clauss method during anticoagulation with bivalirudin. Anesthesiology 2008; 109: 160-161.
    CrossrefPubMedSearch in Google Scholar